Alterations in macular microvasculature in chronic hepatitis B patients measured by optical coherence tomography angiography

Introduction

Chronic hepatitis B (CHB) infection is a global health issue that affects approximately 250 million individuals, with around 1.2 million new cases each year (1,2). It is well known that CHB has the potential to develop into cirrhosis and hepatocellular carcinoma. In addition, CHB is also associated with extrahepatic manifestations, including cryoglobulinemia, glomerulonephritis, serum-sickness-like syndrome, and polyarteritis nodosa (3,4), and with ocular disorders such as uveitis, age-related macular degeneration (AMD), cataract, and dry eye disease (5-8). These extrahepatic manifestations may be attributed to inflammatory responses triggered by circulating immune complex deposition and direct viral cytopathic effects (4,5). Chronic inflammation provides a key pathophysiological basis for microvascular structural and functional impairment; however, the early, subclinical impact of hepatitis B virus (HBV) infection on systemic microcirculation remains poorly understood. Moreover, current research on CHB-related ocular changes has primarily focused on fundus alterations in cirrhotic patients or associations with specific ocular diseases such as AMD and uveitis (5,8,9). Whether macular microvascular alterations occur in patients with pre-cirrhosis CHB remains unexplored.

The retinal microcirculation acts as an inherent window for the investigation of systemic microvascular diseases. Optical coherence tomography angiography (OCTA) is a rapidly advancing imaging technique capable of providing high-resolution images of the macular microvasculature noninvasively, rapidly, and reproducibly. This technology is widely used in the diagnosis of ophthalmic conditions, including AMD and diabetic retinopathy (10), and can also be applied to assess retinal and optic nerve microvascular alterations induced by viral infections (11). In addition to retinal vascular density (VD), the foveal avascular zone (FAZ) is another important OCTA parameter that reflects pathological changes in the central retinal microvasculature (12).

This study aimed to utilize OCTA to quantitatively assess the changes in macular superficial microvascular density in non-cirrhotic CHB patients, and to analyze the correlation between these changes and clinical features such as liver stiffness measurement (LSM) evaluated by transient elastography (TE) and virological markers. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2854/rc).

Methods

Ethics

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Research Ethics Board of Xiangya Hospital (No. 202108151). Written informed consent was provided by all participants prior to enrollment.

Study design and participants

The retrospective cross-sectional study included patients who presented to the Department of Ophthalmology, Xiangya Hospital, Central South University, between January 2015 and August 2021 for routine ophthalmic outpatient appointments due to various eye-related conditions, including refractive errors, dry eye, cataract, and glaucoma. All patients had been diagnosed with CHB prior to their ophthalmic visit, with the initial diagnosis having either been made at Xiangya Hospital or other hospitals. For patients initially diagnosed at Xiangya Hospital, the diagnosis was confirmed by two experienced infectious disease specialists from the Department of Infectious Diseases, Xiangya Hospital, according to the AASLD 2018 Hepatitis B Guidance based on the following criteria (13): (I) hepatitis B surface antigen (HBsAg) positivity for ≥6 months; (II) detectable serum HBV DNA; and (III) normal or elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels, with or without liver biopsy showing chronic hepatitis with variable necroinflammation and/or fibrosis. For patients initially diagnosed at other hospitals, the diagnosis was reviewed and verified by the same two specialists according to the same criteria to ensure diagnostic consistency. A total of 24 eyes of 24 CHB patients and 24 eyes of 24 healthy individuals whose ages were comparable were included. To ensure statistical independence, a single eye from each participant in both the CHB cohort and the control cohort was randomly selected for analysis using a computer-generated random sequence. Every participant underwent a comprehensive ophthalmic assessment performed by the same ophthalmologist. This assessment incorporated the measurement of best-corrected visual acuity (BCVA), intraocular pressure measurement (IOP), slit-lamp microscopy, 90-diopter (D) lens mydriatic fundus examination using 0.5% compound tropicamide eye drops, and OCTA. Individuals meeting any of the following conditions were not included: (I) conditions potentially affecting macular VD measurements, such as severe cataract, glaucoma, corneal disease, or a previous diagnosis of retinal or optic nerve disorders; (II) spherical refractive error exceeding 6.00 D in absolute value and/or cylindrical refractive error exceeding 3.00 D in absolute value; (III) a history of ocular surgery or trauma; (IV) allergy to mydriatic agents or the presence of systemic diseases including hypertension, diabetes, or hyperthyroidism; or (V) presence of autoimmune diseases or systemic vasculitides. No incidental diagnoses of retinal or optic nerve disorders were identified during the ophthalmic assessment. Therefore, no participants were excluded based on these conditions.

Clinical and serological assessment

Clinical data, including height, weight, and body mass index (BMI), were extracted from electronic medical records. Serological markers including HBsAg, hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb), hepatitis B core antibody (HBcAb), hepatitis B core antibody immunoglobulin M (HBcAb-IgM), high-sensitivity HBV DNA quantification, ALT, AST, alpha-fetoprotein (AFP), procollagen type III N-terminal peptide (PIIINP), hyaluronic acid (HA), glycocholic acid (CG), laminin (LN), and collagen type IV (CIV) were assessed at the Department of Clinical Laboratory, Xiangya Hospital. LSM was performed using transient elastography (FibroScan, Echosen™, Paris, France) by trained operators following standard protocols. All clinical and serological data were obtained from the initial diagnosis or diagnostic confirmatory examinations at the Department of Infectious Diseases, Xiangya Hospital. Serological testing, LSM, and ophthalmic evaluation were completed within the same timeframe (within a 3-day interval).

OCTA measurements

All participants underwent macular superficial retinal microvascular imaging using the AngioPlexTM OCTA system (Cirrus; Zeiss, Dublin, USA; software version 10.0.0.14618). The system employs spectral-domain OCTA (SD-OCTA) technology, with a scanning area of 6×6 mm covering the superficial retinal layer from the inner limiting membrane (ILM) to the inner plexiform layer (IPL) (14). Scans with a signal strength index (SSI) below 7 were excluded to ensure adequate image quality. The built-in software automatically quantified two key microvascular parameters: vessel length density (VLD), characterized as the aggregate length of perfused vessels per unit region, and vessel perfusion density (VPD), characterized as the aggregate area of perfused vessels per unit region (15). Analyses were performed within four concentric regions centered on the fovea: the central (a 1 mm in diameter circle centered on the fovea), inner (a 1–3 mm diameter ring), outer (a 3–6 mm diameter ring), and full zones (a 6 mm diameter circle). Each of the inner and outer regions was further subdivided into four quadrants (superior, nasal, inferior, temporal), resulting in a total of 12 zones for analysis: the central region, the full region, the inner zone (IZ), the outer zone (OZ), and the eight quadrants, which were designated as inner superior zone (ISZ), inner nasal zone (INZ), inner inferior zone (IIZ), inner temporal zone (ITZ), outer superior zone (OSZ), outer nasal zone (ONZ), outer inferior zone (OIZ), and outer temporal zone (OTZ) (Figure 1) (16). Additionally, the system automatically measured three morphological metrics of the FAZ: area, perimeter, and circularity index. The FAZ circularity quantifies deviation from an ideal circle, where a value of 1 corresponds to an ideal circle and values approaching 0 reflect increasing irregularity. FAZ morphology thereby serves as an indicator of the structural integrity of the perifoveal capillary network (17).

Figure 1 OCTA imaging and schematic illustration of macular zones. (A) Representative OCTA image of the macular region in a non-cirrhotic CHB patient. (B) Schematic illustration of the macular zones. The scanning area was partitioned into concentric circles centered on the fovea, comprising the central zone (1 mm diameter circle), the inner zone (1–3 mm diameter ring), the outer zone (3–6 mm diameter ring), and the full region (6 mm diameter circle). Each of the inner and outer zones was further subdivided into four quadrants (superior, nasal, inferior, temporal). CHB, chronic hepatitis B; IIZ, inner inferior zone; INZ, inner nasal zone; ISZ, inner superior zone; ITZ, inner temporal zone; OCTA, optical coherence tomography angiography; OIZ, outer inferior zone; ONZ, outer nasal zone; OSZ, outer superior zone; OTZ, outer temporal zone.

Statistical analysis

All statistical analyses were carried out utilizing the software SPSS 29.0 (IBM Corp., Armonk, NY, USA). To evaluate normality of continuous variables, the Shapiro-Wilk test was utilized in combination with visual inspection of Q-Q plots and histograms. Data that followed a normal distribution were presented as mean ± standard deviation, whereas data that did not follow a normal distribution were presented as median (interquartile range). Based on the data distribution and variance, parametric or non-parametric tests were used to compare continuous variables between the two groups. For data that met the assumptions of normality and homogeneity of variance, the independent samples t-test was used, whereas the Mann-Whitney U test was applied to data that violated these assumptions. The chi-square test was used to compare categorical variables. A P value less than 0.05 was regarded as statistically significant. For OCTA parameters that showed significant differences between the CHB group and the healthy controls (HC), we further analyzed the correlations between these parameters and clinical characteristics within the CHB group. Pearson correlation coefficients were used for data following a normal distribution, whereas Spearman rank correlation coefficients were applied for data deviating from normality.

Results

Clinical characteristics and parameters of the enrolled individuals

The study included 48 eyes from 48 participants: 24 from CHB patients and 24 from healthy individuals whose ages were matched. Their clinical characteristics and ocular parameters are presented in Table 1. The two groups showed no statistically significant differences in age, sex, BCVA, IOP, eye laterality, or SSI (P≥0.09).

Comparison of OCTA parameters between CHB patients and HC

Macular microvascular parameters are presented in Table 2 and visualized as boxplots in Figures S1-S4. Compared with the HC, CHB patients showed significantly higher VLD and VPD in both the OZ and OSZ. Specifically, in the OZ, CHB patients had higher VLD [18.35 (17.83–19.35) vs. 17.50 (16.35–18.87), P=0.026) and VPD [0.46 (0.44–0.48) vs. 0.43 (0.40–0.47), P=0.044] compared with HC. In the OSZ, CHB patients also showed higher VLD [18.65 (17.63–19.48) vs. 17.50 (16.73–18.40), P=0.014] and VPD [0.47 (0.44–0.48) vs. 0.44 (0.40–0.46), P=0.003]. No significant statistical differences were found in VLD or VPD in any of the remaining zones. Furthermore, there was no substantial difference between the two groups in the morphological characteristics of the FAZ, including area, perimeter, and acircularity index (all P>0.05).

Analysis of correlations between OCTA metrics and other clinical characteristics in CHB patients

To examine the potential influence of other clinical features on elevated macular microvascular parameters in patients with CHB, correlation analyses were performed. Spearman’s rank correlation analysis revealed that serum HBeAg levels showed significant negative correlations with VLD in the OZ and OSZ, as well as with VPD in the OZ (rs =−0.665, P=0.003; rs =−0.475, P=0.046; rs =−0.632, P=0.005, respectively) (Table 3). Similarly, HBeAb levels were negatively correlated with both VLD and VPD in the OZ (rs =−0.644, P=0.004; rs =−0.620, P=0.006) (Table 3). In contrast, LSM was positively correlated with both VLD and VPD in the OZ (rs =0.482, P=0.031; rs =0.519, P=0.019) (Table 3). Other OCTA parameters were not included in the correlation analysis, as they did not show significant differences between the CHB and controls.

Discussion

The study provides the first evidence that patients with CHB who have not progressed to cirrhosis exhibit significantly elevated superficial VLD and VPD in the OZ and OSZ. Further correlation analysis revealed that both VLD and VPD in the OZ were positively correlated with LSM, while showing negative correlations with serum levels of HBeAg and HBeAb. Therefore, we propose a unifying hypothesis to explain our findings: CHB-associated systemic inflammation may drive compensatory retinal microvascular remodeling through circulating inflammatory mediators, manifesting as increased VD. This framework explains three key observations:

First, elevated VD in CHB patients compared to controls may reflect systemic inflammatory activity rather than isolated hypoxia. Retinal blood flow is regulated by local autoregulation in response to metabolic demand. Specifically, systemic hypoxia induces vasodilation and increased perfusion, whereas hyperoxia leads to vasoconstriction (18). Previous studies have confirmed that systemic hypoxia increases VD in the superficial vascular plexus (19,20). However, in our study, retinal VD showed a positive correlation with LSM, which is a composite marker reflecting both hepatic inflammation and fibrosis (21,22). This suggests that the observed microvascular changes may be driven by systemic pathological processes linked to CHB disease activity. Within the context of persistent HBV infection, the liver continually releases inflammatory mediators, including transforming growth factor-β (TGF-β), interleukin (IL)-6, tumor necrosis factor-α (TNF-α), IL-1β, connective tissue growth factor (CTGF), high mobility group box 1 (HMGB1), and IL-8, into the systemic circulation (23-25). These circulating cytokines can disrupt endothelial integrity, increase vascular permeability, and promote angiogenic activity (26-31), which may ultimately result in retinal vasodilation and increased perfusion. Notably, these VD elevations were predominantly concentrated in the OZ and OSZ, suggesting that these regions may represent the initial sites of inflammation-induced retinal microvascular remodeling in non-cirrhotic CHB.

Second, the positive correlation between VD and LSM suggests that microvascular changes may be positively related to the degree of hepatic inflammation. Persistent inflammation plays a dominant role in both triggering and maintaining liver fibrosis in CHB (23). LSM measured by TE simultaneously reflects the degree of liver fibrosis and the level of active necroinflammation (21,22). As discussed above, within the context of persistent HBV infection, the liver continually releases inflammatory mediators into the systemic circulation (23-25). Prior studies have shown that these circulating cytokines can disrupt endothelial integrity, increase vascular permeability, and promote angiogenic activity (26-31). Thus, we speculate that the systemic inflammation associated with CHB may induce compensatory remodeling of the retinal microvasculature via these circulating cytokines, which may be visualized as an increase in VLD and VPD on imaging.

Third, the negative correlations between VD and both HBeAg and HBeAb may reflect the transition from immune tolerance to immune clearance. In the natural history of CHB, high HBeAg signifies the immune-tolerant phase, characterized by “high viral replication, low inflammation” with normal ALT and absence of significant liver injury (32-35). The subsequent decline of HBeAg marks the transition to the immune-clearance phase, which features elevated ALT, enhanced immune activation, and increased systemic inflammation (35-37). In our study, both HBeAg and HBeAb levels showed negative correlations with retinal VD. It should be noted that HBeAb was detected using a competitive assay (>1 S/CO indicates negativity); therefore, a higher reported value corresponds to a lower actual antibody level and a weaker immune response. Thus, lower HBeAg and higher actual HBeAb indicate heightened immune-inflammatory activity, which may drive retinal microvascular remodeling.

The positive correlation observed between retinal microvascular density and LSM carries important potential implications. It further elucidates the pathophysiological significance of LSM assessed by TE: they reflect not only the degree of accumulated liver fibrosis but also the extent of hepatic necroinflammation. Notably, the early decline in LSM following antiviral therapy primarily corresponds to the alleviation of inflammation rather than the reversal of fibrosis (38,39). Future longitudinal studies could evaluate whether OCTA-derived metrics, alongside LSM, can reflect treatment-induced reduction in inflammation and liver stiffness.

In summary, systemic inflammation associated with CHB may mediate compensatory remodeling of the retinal microvasculature through circulating cytokines. This finding suggests that OCTA parameters may serve as potential non-invasive biomarkers for indirectly evaluating hepatic inflammatory activity in non-cirrhotic CHB patients. Moreover, this mechanistic framework may partly explain the increased epidemiological risk of ocular disease including uveitis and AMD among CHB-infected patients (5,8). Further validation through larger-scale prospective longitudinal studies is warranted.

This study has several limitations. Firstly, the sample size was limited (24 eyes per group), which may affect statistical power and limit the generalizability of the findings. All participants were in the non-cirrhotic stage of CHB, so the results may not apply to patients with cirrhosis. Secondly, the cross-sectional design precludes causal inferences and cannot establish the predictive value of OCTA parameters for disease progression or clinical outcomes. Future longitudinal prospective cohort studies incorporating larger sample sizes and patients across the full disease spectrum, including those with cirrhosis, are needed to better clarify the long-term impact of CHB on retinal microvasculature. Thirdly, the current analysis focused only on the superficial retinal vascular parameters (VLD and VPD) in the macular region. Notably, the observed microvascular alterations were confined to the OZ and OSZ, whereas other macular regions showed no significant differences. Further research should extend to evaluating changes in the deep retinal capillary plexus and the choroidal vascular system to provide a more complete understanding of the pathological effects of CHB infection on different vascular layers of the eye.

Conclusions

This study provides the first evidence that patients with non-cirrhotic CHB exhibit significantly increased macular superficial microvascular density, predominantly in the OZ and OSZ. These microvascular alterations positively correlate with LSM (reflecting hepatic inflammation and fibrosis) and negatively correlate with HBeAg levels (reflecting the transition from immune tolerance to immune clearance). We propose that CHB-associated systemic inflammation drives compensatory retinal microvascular remodeling through circulating inflammatory mediators. OCTA parameters may serve as potential non-invasive biomarkers for assessing hepatic inflammatory activity in non-cirrhotic CHB patients.

Acknowledgments

The authors gratefully acknowledge the dedicated efforts of the medical and technical staff of the Eye Center of Xiangya Hospital.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2854/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2854/dss

Funding: This work was supported by the Hunan Natural Science Foundation (No. 2019JJ40528), which was awarded to H.X.; the National Natural Science Foundation of China (No. 81600713), which was awarded to J.Z.; and the Hunan Provincial Natural Science Foundation Regional Joint Fund (No. 2024JJ7633), which was awarded to Y.D.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1-2854/coif). H.X. declares receipt of funding support from the Hunan Natural Science Foundation (No. 2019JJ40528). Y.D. declares receipt of funding support from the Hunan Provincial Natural Science Foundation Regional Joint Fund (No. 2024JJ7633). J.Z. declares receipt of funding support from the National Natural Science Foundation of China (No. 81600713). The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Research Ethics Board of Xiangya Hospital (No. 202108151). Informed consent was obtained from all individual participants involved in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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